We have studied several aspects of the action of psychotropic drugs. In cultured cerebellar granule cells carbamazepine (CBZ) was found to induce a dose-dependent delayed toxicity in a concentration range that overlaps and largely exceeds the therapeutic level. This neurotoxicity may be involved in the side effects and overdosage toxicity of CBZ. Additionally, glutamate induces neuro- toxicity of cerebellar granule cells by activation of NMDA receptors. The neurotoxicities induced by CBZ or glutamate are completely blocked by the presence of NMDA. The neuroprotective effect of NMDA is not due to desensitization of NMDA receptors. Carbamazepine-induced neurotoxicity may be due to allosteric interaction of this drug with certain specific domains of NMDA receptors. Another psychotropic drug, lithium, at clinically relevant concentrations (equal to or less than 2 mM) was found to be neurotrophic for cerebellar granule cells. Following a 7-day treatment, the outgrowth of neurites as well as the expression of mRNAs for m3-muscarinic receptors and c-fos were markedly enhanced. At higher concentrations (equal to or greater than 5 mM), this drug elicited a deterioration of neuronal morphology due to lithium-induced neurotoxicity. In a collaborative effort, we found that in rats chronically treated with haloperidol, the phosphoinositide hydrolysis mediated by several neurotransmitter receptor systems were down-regulated, resembling the known effects of lithium. Moreover, combined treatment with nicotine abolished haloperidol's effect on carbachol-induced phosphoinositide turnover in the cortex and hippocampus, but potentiated the same response in the striatum. We also examined the effects of long-term treatment of rats with lithium and CBZ on the mRNA level for connexin43, a major gap junction protein. Lithium but not CBZ tends to reduce connexin43 mRNA levels in most brain regions; however, in the hippocampus, CBZ but not lithium has this effect.